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PMID: 16724925 Published · ppublish English Journal Article Review

Evolution and function of the NR1I nuclear hormone receptor subfamily (VDR, PXR, and CAR) with respect to metabolism of xenobiotics and endogenous compounds.

Current drug metabolism ·Vol. 7 ·No. 4 ·2006-05-00 ·Pages 349-65

Reschly EJ, Krasowski MD

Abstract

The NR1I subfamily of nuclear hormone receptors includes the 1,25-(OH)(2)-vitamin D(3) receptor (VDR; NR1I1), pregnane X receptor (PXR; NR1I2), and constitutive androstane receptor (CAR; NR1I3). PXR and VDR are found in diverse vertebrates from fish to mammals while CAR is restricted to mammals. Current evidence suggests that the CAR gene arose from a duplication of an ancestral PXR gene, and that PXR and VDR arose from duplication of an ancestral gene, represented now by a single gene in the invertebrate Ciona intestinalis. Aside from the high-affinity effects of 1,25-(OH)(2)-vitamin D(3) on VDRs, the NR1I subfamily members are functionally united by the ability to bind potentially toxic endogenous compounds with low affinity and initiate changes in gene expression that lead to enhanced metabolism and elimination (e.g., induction of cytochrome P450 3A4 expression in humans). The detoxification role of VDR seems limited to sensing high concentrations of certain toxic bile salts, such as lithocholic acid, whereas PXR and CAR have the ability to recognize structurally diverse compounds. PXR and CAR show the highest degree of cross-species variation in the ligand-binding domain of the entire vertebrate nuclear hormone receptor superfamily, suggesting adaptation to species-specific ligands. This review examines the insights that phylogenetic and experimental studies provide into the function of VDR, PXR, and CAR, and how the functions of these receptors have expanded to evolutionary advantage in humans and other animals.

MeSH Terms
Animals Constitutive Androstane Receptor Genetic Variation Humans Ligands Pregnane X Receptor Receptors, Calcitriol/metabolism Receptors, Cytoplasmic and Nuclear/metabolism Receptors, Steroid/metabolism Transcription Factors/metabolism Xenobiotics/metabolism
Chemicals
Constitutive Androstane Receptor Ligands NR1I2 protein, human NR1I3 protein, human Pregnane X Receptor Receptors, Calcitriol Receptors, Cytoplasmic and Nuclear Receptors, Steroid Transcription Factors Xenobiotics
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Reschly E J
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Krasowski Matthew D
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Article Info
Journal
Current drug metabolism
Abbr.
Curr Drug Metab
ISSN
1389-2002
DOI
10.2174/138920006776873526
Published
2006-05-00
Pages
349-65
Language
English
Region
Netherlands
NLM ID
100960533
PMCID
PMC2231810
Subset
IM
Grants
NIGMS NIH HHS · K08 GM074238 · United States
NIGMS NIH HHS · K08 GM074238-01A1 · United States
External Links
PubMed source DOI: 10.2174/138920006776873526 PMC Full Text View journal details
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